Recombinant tissue-type plasminogen activator (tPA) is currently the only approved pharmacological agent for the treatment of ischemic stroke, and in general it must be administered within 4.5 hours of symptom onset. Because of this time constraint, as well as dangers associated with this drug, it is estimated that only about 5- 10% of stroke patients are treated with tPA. There is thus a significant need for new and effective approaches to treat stroke. It is now clear that the complement system plays an important role in the propagation of inflammation and injury following cerebral ischemia and reperfusion (ischemic stroke), and the overall goal of this project is to develop and characterize a novel, effective and safe strategy of site-targeted complement inhibition that can be applied several hours after stroke, and that will improve long-term cognitive and functional recovery. To identify the most effective complement inhibitory approach, we will prepare and characterize various complement inhibitors that block different parts of the complement pathway and that are targeted to the site of ischemic brain injury via a novel approach. The constructs will be investigated using a mouse model of middle cerebral artery occlusion and reperfusion, and we will investigate the effect of our constructs on cerebral injury, repair and neuroregeneration, and acute and chronic cognitive and motor function outcomes. Following identification of the optimum type of complement inhibitory construct, we will complete a series of pre-clinical determinations that will assist in future drug development. These studies will include PK and PD determinations, dose response, treatment window, dosing schedule, and effect in young and aged mice (since the risk of stroke increases with age). Finally, we will investigate our strategy of complement inhibition in the context of tPA therapy to determine whether there are any adverse effects associated with co-administration of the two pharmacological reagents.